Molecular Determinants of Myeloma Bone Disease and Uses Thereof

Abstract

The present invention is drawn to understanding lytic bone diseases. In this regard, the present invention discloses mechanism by which Wnt signaling antagonist inhibits bone differentiation. Also disclosed herein are methods for treating multiple myeloma, for restoring osteoprotegerin (OPG) expression in a cell, for inhibiting receptor activator of nuclear factor kappa B ligand (RANKL) expression in a cell, and for increasing bone mass in a subject. These methods utilize a DKK1 neutralizing antibody, an anti-sense oligonucleotide against a DKK1 gene, or a shRNA against a DKK1 gene to inhibit the activity of the DKK1 protein.

What is claimed is: 
     
         1 . A method for treating a multiple myeloma in an subject, wherein the multiple myeloma is characterized by increased DKK1 expression or activity in a subject, comprising the step of:
 administering to the subject an amount of an anti-DKK1 antibody that is pharmacologically effective to inhibit an activity of the DKK1 protein.   
     
     
         2 . The method of  claim 1 , wherein the multiple myeloma is smoldering myeloma, solitary plasmacytoma, diffused multiple myeloma, multiple myeloma with osteopenia, newly diagnosed multiple myeloma, or focal multiple myeloma. 
     
     
         3 . The method of  claim 1 , wherein the treatment of the subject with an anti-DKK1 antibody inhibits myeloma growth. 
     
     
         4 . The method of  claim 1 , wherein the DKK-1 protein is encoded by the DKK1 gene of SEQ ID NO: 47. 
     
     
         5 . A method for restoring osteoprotegerin (OPG) expression in a cell, comprising the step of:
 contacting the cell with a DKK-1 neutralizing antibody, an anti-sense oligonucleotide against a DKK-1 gene, or a small hairpin RNA (shRNA) against a DKK-1 gene, wherein the contacting agent inhibits the activity of the Dkk1 protein.   
     
     
         6 . The method of  claim 5 , wherein the DKK1 protein is encoded by the DKK1 gene with a sequence shown in SEQ ID NO: 47. 
     
     
         7 . The method of  claim 5 , wherein the shRNA binds to the sequence consisting of SEQ ID NO: 45 in the DKK1 gene sequence. 
     
     
         8 . A method for inhibiting receptor activator of nuclear factor kappa B ligand (RANKL) expression in a cell, comprising the step of:
 contacting the cell with a DKK1 neutralizing antibody, an anti-sense oligonucleotide against a DKK1 gene, or a shRNA against a DKK1 gene, wherein the contacting agent inhibits the activity of the DKK1 protein.   
     
     
         9 . The method of  claim 8 , wherein the DKK1 protein is encoded by the DKK1 gene with a sequence shown in SEQ ID No: 47. 
     
     
         10 . The method of  claim 8 , wherein the shRNA binds to the sequence consisting of SEQ ID NO: 45 in the DKK1 gene sequence. 
     
     
         11 . A method for increasing osteoblast activity in a subject exhibiting increased DKK1 activity or expression, comprising the step of:
 administering to the subject an agent that is a DKK1 shRNA that binds a DKK1 protein consisting of the sequence encoded by the DKK1 gene consisting of the sequence shown in SEQ ID NO: 45, wherein the agent inhibits the activity of the DKK1 protein.   
     
     
         12 . The method of inhibiting osteoclast activity in an individual, exhibiting increased DKK1 activity or expression, comprising the step of:
 administering to the subject an agent that is a DKK1 shRNA that binds DKK1 protein consisting of the sequence encoded by the DKK1 gene consisting of the sequence shown in SEQ ID NO: 45, wherein the agent inhibits the activity of the DKK1 protein.   
     
     
         13 . The method of increasing bone mass in a subject, exhibiting increased DKK1 activity or expression, comprising the step of:
 administering to the subject an agent that is a DKK1 shRNA that binds a DKK1 protein consisting of the sequence encoded by the DKK1 gene consisting of the sequence shown in SEQ ID NO: 45, wherein the agent inhibits the activity of the DKK1 protein.